Therapeutic system which can be moisture-activated

ABSTRACT

This invention provides for a therapeutic system for timed and controlled release of at least one therapeutic active agent to a human or animal organism by diffusion through the skin or mucous membrane. The active agent is initially present, for the purposes of manufacture and storage, in a first state in the form of a pharmaceutically acceptable salt, which is chemically stable and insufficiently permeable for the skin or mucous membrane. The active agent is converted at the application site upon access of moisture and by an activating agent into a second state, which is suitable for diffusion through the skin or mucous membrane and in which it is taken up by the organism. The activating agent is initially present as a solid substance or a mixture or a plurality of such substances, which reacts in aqueous solution as an acid or base. The activating agent contains a portion of water of at least 5% in its solid body structure, either intercalated or bound thereto.

This application is a 371 of PCT/EP99/01802 filed Mar. 18, 1999. Thisapplication claims priority to German application No. 198 14 087.8 filedMar. 30, 1998.

This invention relates to a therapeutic system for timed andquantity-controllable release of at least one therapeutically activesubstance to a human or animal organism by means of diffusion throughthe skin or mucous membrane, with said active substance, for manufactureand storage, being initially present in a first state in which it ischemically stable and Insufficiently permeable for the skin or mucousmembrane, whereas at the site of application it is converted into asecond state by access of moisture, in which state it is suitable fordiffusion through the skin or mucous membrane and taken up by theorganism.

Grounds for utilising an activatable system exist in all those caseswhere that chemical state of an active sub stance which is most suitablefor delivery to the body is not identical with the state which isoptimally suitable for the production and storage of a therapeuticssystem.

Therapeutic systems activated by moisture are known and have beedescribed, for example, in U.S. Pat. No. 4,781,924; EP 0 316 065 B1; DE38 81 340.

Only part of these documents relate to moisture-activated systems inwhich activation involves the chemical con version of the active agent.

These comprise, for instance, systems wherein active substance isinitially present in a state which is not capable of diffusing throughthe surface of the system in quantities per unit of time which aresufficient for therapeutic purposes.

Apart from the active agent it is therefore necessary to use an“activating agent” which in its first state is water-free while, underabsorption of moisture, it is transferred into a second, hydrated anddissolved state. In the dissolved state, the activating agent is thencapable of transforming active agent into a second form which is able todiffuse through the surface of the system in therapeutically sufficientquantities per unit of time.

Moreover, in the aforementioned documents there is described a structureof systems wherein the activator is present from the start in dissolvedstate but enclosed in microcapsules which in the initial state do notrelease the activator to the environment. Activation involves thedestruction of the microcapsules, preferably by breaking or melting.Activation by skin moisture is not described for this modification. Theknown systems are complicated in terms of their structure and therebycause comparatively high manufacturing costs whilst in part resulting ina dissatisfactory activation process.

Starting from the aforementioned prior art, it is the object of thepresent invention to simplify moisture-activatable systems and therebyto reduce production costs. It is a further aspect of the object toaccelerate the activation process, as well as to attain an increase ofthe release rate of active substance from such systems.

These objects are surprisingly achieved according to the presentinvention, a therapeutic system for timed and controlled release of atleast one therapeutic active agent to a human or animal organism bymeans of diffusion through the skin or mucous membrane, said activeagent initially being present, for the purposes of manufacture andstorage, in a first state in which it is chemically stable andinsufficiently permeable for the skin or mucous membrane, whereas it isconverted at the application site into a second state by access ofmoisture, in which state it is suitable for diffusion though the skin ormucous membrane and in which it is taken up by the organism,characterized in that said active agent in said first state is containedin the system as a pharmaceutically acceptable salt which upon access ofmoisture and by means of an activating agent, which is likewisecontained in the system, is chemically converted into the said secondstate of an acid or base which is taken up through the skin or mucousmembrane into the organism in an accelerated manner and in greaterquantities compared to the salt form, said activating agent being asolid substance reacting in aqueous solution as an acid or base, or amixture of a plurality of such substances, and containing a portion ofwater of at least 5% in its solid body structure, either intercalated orbound thereto. Due to the activator being present in the system neitherin the water-free nor in the dissolved state, but instead being employedin a hydrated but undissolved chemical state, preferably in the form ofthe hydrates of the activator, these hydrates possess a crystallinestate of order and, in this state, entrain water in a defined quantityratio in addition to the activator. This hydrated form of the activatoris present in the system as an undissolved solid. This undissolved formis practically incapable of converting the active substance from a firstchemical state into a second one. It is dissolved only upon access ofskin moisture and then becomes active with respect to the activesubstance in the desired manner. By the water which is entrained withinthe crystal of the activator from the start, the process of activationis accelerated and markedly improved in its overall extent.

The system according to the invention is preferably used in themanufacture of transdermal therapeutic systems (TTSs). Since theactivator is inactive in the undissolved state, it is even possible toincorporate active agent and activator in one and the same layer of aTTS, which layer may at the same time also possess pressure-sensitiveadhesive properties.

Especially by means of this latter “drug-in-adhesive” structure, it ispossible to release the active substance astonishingly quickly and inlarge amounts, even if the water-free forms of the activator areutilised.

In this way it is possible to realise simplified TTS structures while atthe same time enabling accelerated and increased active substancedelivery.

The changeable chemical states specifically concern the acid-baseequilibrium in which the active substance in question is present.

Among the active agents used there is a large number of compoundscontaining acidic or basic reacting molecule groups; the great majorityof these have basic characteristics.

The basic groups are typically primary, secondary or tertiary amines.These functional groups are reactive and can take part in a plurality ofreactions (e.g. oxidation processes) which are apt to result indegradation of the active substance.

If these groups are transformed into a salt by reacting with an acid,this very frequently leads to a marked improvement of chemicalstability.

Furthermore, the salts generally have higher melting points than thefree bases. It is even possible for a base which is present as a liquidat room temperature to be transformed into the solid state by conversioninto a salt. Apart from raising the melting point, salt formation alwaysresults in a reduction of volatility.

Finally, salt formation practically always leads to a marked increase inthe water-solubility whereas, in parallel thereto, there occurs a clearreduction in the solubility in organic solvents.

The aforementioned properties of the salts of basic active agents leadto the fact that in pharmaceutics research and development, in a greatmajority of cases the salt of a basic active substance is givenpreference as a raw material to the free base.

For the development of TTSs this often affords an advantage due to thehigher stability of the salts.

Of particular significance are, however, also the increased meltingpoint and the diminished volatility of the salt form, especially sincemany processes for the manufacture of TTSs always include one segmentinvolving markedly increased operating temperature typically in therange of between 60 and 120° C.

Where solvent-containing coating methods are employed, this is thedrying step for removing the solvents required in the process. In thecase of the solvent-free hot-melt process, the product mass istemporarily heated strongly in order to reduce viscosity.

As a consequence, in the production of TTSs there are very likely tooccur problems where a low-melting and/or volatile active agent in theform of a free base is used. The salt forms offer considerableadvantages in this respect.

In light of the aforementioned aspects, it is frequently desirably inTTS development to process an active agent in its salt form.

However, the active substance salts are little suited for transcutaneousadministration, as compared to the non-salt forms. For example, thebarrier of the human skin is predominantly of lipophile character. Theskin is thus almost impermeable to strongly polar, water-solublecompounds, which is why the conversion of an active agent to a salt isin almost all cases accompanied by a deterioration of the absorption viathe skin.

This frequently leads to contradictory demands being placed on theactive substance which cannot be met by one of its chemical statesalone.

A solution to the problem are activatable forms of TTSs. Activation of aTTS in this context means that the salt form of the active substancecontained in the TTS is used, which is favourable with respect toprocessing and storage, and that this salt is converted into thenon-salt form, which is characterized by its better ability to permeatethe skin, only upon the later application of the TTS and under certainexternal influences. Among the possible external influences, theabsorption of moisture after application to the skin surface is takeninto consideration with preference.

The human skin releases moisture in two ways: Through the outermost skinlayer, called epidermis, there takes place a continuous, passive escapeof water vapour caused by diffusion—the transepidermal loss of water.Via the sweat glands, water vapour is, by contrast, released actively,and in the case of more intense perspiration, water even emerges inliquid form from the skin surface.

A TTS which is applied to the skin is subjected to this emerging skinmoisture, and, depending on its constitution, may absorb smaller orgreater amounts of moisture.

Important in this respect is the outer backing layer of a TTS, whichfaces away from the skin. The less water vapour-permeable the backinglayer, the more pronounced is the accumulation of moisture retained inthe TTS, until finally occlusion results.

This accumulation of moisture can be made use of for activating achemical conversion reaction.

Two water-soluble or at least water-swellable reaction partners A and Bwhich are present in the TTS in dry, practically undissolved form canreact with each other only after access of moisture, with the substancesbeing dissolved or at least solvated.

This principle is generally known from effervescent tablets, which onlyupon access of water form carbon dioxide in an acid-base reaction.

In the case of an acid-base reaction, water is required merely assolvent for the reactants. It is, however, not consumed in the reaction.A small amount of water therefore suffices to start and continuouslymaintain the process.

To now release the active substance, which is present in the form of asalt, from the salt in an acid-base reaction, a reaction partner isrequired, designated here as activator.

Therapeutic systems making use of this activation principle have alreadybeen described in the above-cited U.S. Pat. No. 4,781,924, EP 0 316 065B1, DE 38 81 340.

However, the inventors here started from the assumption that theactivating agent must be present in an expressly water-free state.

The activating agent is hydrated, or dissolved, only in a second stateafter having absorbed moisture during application of the system, oralternatively after having absorbed moisture from a reservoir within thesystem.

It was now surprisingly found that it is not necessary to store theactivator in the system in a water-free form. Even if the activator ispresent in a hydrated, but undissolved form, almost no reaction with theactive substance salt takes place during the manufacture and storage ofthe system

Many activators which are suitable as auxiliary agents typically do notoccur in water-free form at all. They must first be dried or purchasedin the (frequently more expensive) water-free form, and must be storedcorrespondingly. This applies, for example, to the substances of sodiumcarbonate, sodium monohydrogen phosphate and sodium orthophosphate,which in their water-free form are even hygroscopic.

The corresponding disadvantages are not present if the hydrated formsare used.

An activator that is already present in the system in hydrated form ismoreover advantageous even in respect of the course of activation uponaccess of moisture. It was found that when using already hydratedactivators, the speed and extent of the activation process are improvedas compared to the water-free activators.

This process is not to be confused with a procedure described in WO94/07468, according to which the active substance in its water-solublesalt form and an inorganic silicate are initially mixed with each otherin water, this aqueous solution is incorporated in a polymer solutionand from this solution there are manufactured TTSs. After a drying step,these TTSs contain, according to the invention, the silicate in hydratedform intimately mixed with the active agent as internal disperse phasein a surrounding polymer. Here, the water-soluble active substance isaccording to the invention even partially dissolved in the aqueous phaseof the silicate.

In contrast thereto, the systems according to the present inventioncomprise only structures wherein active agent and activator are presentseparate from each other, in a joint matrix or in different matrices. Adispersing agent is not necessarily contained.

Suitable activators with water-containing crystalline structure areinorganic or organic compounds which in aqueous solution react as anacid or base.

For converting the basic-reacting state of an active substance into theacid-reacting state, an acid-reacting activator is employed.Basic-reacting activators, by contrast, serve to transform theacid-reacting state of the active agent into the basic-reacting form.

Suitable basic-reacting activators are the following compounds (withoutclaim to exhaustiveness):

basic silicates, basic phosphates, citrates, tartrates, succinates,basic salts of ethylenediaminetetraacetic acid, carbonates, hydrogencarbonates and hydroxides.

These compounds are utilised as alkali, alkaline earth or aluminiumsalts.

Also possible are compounds which are composed of more than one of theaforementioned anions and more than one of the aforementioned metalcations at the same time in a crystalline-defined mixed state. It isalso possible for the aforementioned anions and cations in the crystallattice to be combined with further ions, not mentioned here. Suitableacid-reacting activators are the following compounds (without claim toexhaustiveness):

dihydrogen phosphate, citric acid and dihydrogen citrate, tartaric acidand hydrogen tartrate, trihydrogen salts of ethylenediaminetetraaceticacid, as well as hydrogen sulfates.

These compounds are optionally used as alkali, alkaline earth oraluminium salts.

All such activators are preferably used in a form which in thecrystalline state entrains defined constituent amounts of water. In oneembodiment of the invention, the activating agent is a solid substancereacted in an aqueous solution as an acid or base, or a mixture of aplurality of such substances, and containing a portion of water of atleast 5% in its solid body structure, either intercalated or boundthereto.

Mixtures of different activators are also possible and can be useful foradjusting a certain activation behaviour. The mixture may also comprisecrystalline states of one and the same activator which contain differentquantities of water, in order to modulate the activation behaviour.

Using a mixture of various activators may also be useful if the activesubstance is unstable when exposed to bases which are too strong. Bymeans of the mixture it is possible in such cases to set an optimumbetween desired, activating, and unwanted, disintegrating influences.

The great majority of today's pharmaceutical active substances are basicwhereas acid substances are the minority.

Basic active substances are very frequently used in the form of their,chemically more stable and non-volatile, water-soluble salts. These are,for instance, the hydrochlorides and sulfates.

Since the free bases generally have a greater capacity for penetratingthe skin than the ionic salts, the conversion of the salts of basicactive agents into the free active substance bases is of particularimportance. This conversion can be performed using a basic activator ina moisture-activatable TTS.

Basic activators are therefore given special consideration in thepresent invention:

Among the possible basic activators, the silicates and phosphates areespecially suitable.

Among the silicates, sodium metasilicate pentahydrate as well as thehydrated forms of sodium trisilicate are used preferably.

Also particularly suitable are the hydrates of magnesium trisilicate,typically the pentahydrate.

Among the phosphates, the basic monohydrogen phosphates andorthophosphates as well as the pyrophosphates are suitable. These are,in particular, disodium monohydrogen phosphate dihydrate, heptahydrateand dodecahydrate, as well as trisodium phosphate hexahydrate anddodecahydrate. Also suitable are tetrasodium diphosphate decahydrate.Furthermore, tripotassium phosphate monohydrate and trihydrate as wellas magnesium hydrogen phosphate trihydrate are considered.

Of particular interest are furthermore those activators which have aninternal buffer system and thus show only controlled basic reaction.

This applies especially to the compounds magnesium carbonate hydroxideand aluminium magnesium hydroxide sulfate, which, as acid-bindingagents, can also be internally taken by humans. Both compounds can occurin various compositions which due to their water content in the crystalare well suited for the manufacture of the TTSs according to the presentinvention.

As a representative of the aluminium magnesium hydroxide sulfate,magaldrate (INN) is mentioned here. According to indications made in USP23, this is a product of varying composition having the general formulaAl₅Mg₁₀(OH)₃₁(SO₄)₂.xH₂O

As a representative of magnesium carbonate hydroxide stands hydrotalcite(INN). According to indications in the Merck-Index (12th edition 1996),magnesium carbonate hydroxide generally is (MgCO₃)₄ Mg(OH)₂.5H₂O; andhydrotalcite, in particular, is Al₂O₃ 6MgO CO₂.12H₂O.

In addition to these examples from inorganic chemistry, the followingorganic-based activators are mentioned: trisodium citrate dihydrate(C₆H₅Na₃O₇.2H₂O), magnesium citrate tetradecahydrate(C₁₂H₁₀Mg₃O₁₄.14H₂O), tetrasodium edetate dihydrate(C₁₄H₁₂N₂Na₄O₈.2H₂O), potassium sodium tartrate tetrahydrate(C₄H₄KNaO₆.4H₂O) and disodium succinate hexahydrate (C₄H₄Na₂O₄.6H₂O).

When selecting a suitable activator, dehydrating temperatures generallyplay an important role. Common processes for manufacturing a TTS as arule comprise a drying process in the case of solvent-containing coatingprocesses, or alternatively a melting process if the TTSs aremanufactured in a hot-melt process.

The temperature-dependent, complete release of water from the activatorshould, if possible, lie above these processing temperatures, that is,the processing temperatures should be maintained below the temperatureof complete dehydration of the activator.

The difference should be at least 1–5° C., better still 5–20° C., andideally more than 20° C.

In light of this aspect the silicates and phosphates are particularlysuitable among the aforementioned activators.

The structure of moisture-activatable transdermal therapeutic systemsutilising hydrated activators can be varied in many ways. This isillustrated in FIG. 1–13, which are not true to scale but show examplesof layered structures.

In the most simple and at the same time preferred structure, the activeagent, in a salt form suitable for manufacture and storage of the TTS,as well as the activator, in undissolved state, are present in one andthe same layer of the TTS.

In another construction, active substance and activator are incorporatedin separate layers.

In all cases, it is possible to implement control layers. These controllayers are either inserted between the active substance and theactivator, or they are disposed between the active substance andactivator reservoir and the skin surface.

In the first case, the access of the activator to the active substance,after moisture absorption and dissolution, is controlled, oralternatively the access of the active substance, after moistureabsorption and dissolution, to the activator.

In the second case, the release, after moisture absorption, of theactive substance in its already activated, skin-penetrating form to theskin surface is controlled. Alternatively, the control layers may effectthe control of the moisture absorption of the overall system or ofindividual layers thereof.

Suitable for control in the above sense are those layers whose watervapour-permeability is below the rate per time at which moisture istypically delivered by the skin.

To achieve an activation by moisture, in all of the aforementionedstructures, water or water vapour emerging from the skin must beretained in the TTS. The backing layer of the TTS is thereforepreferably adapted to be water vapour-impermeable.

This is a property, in particular, of films of polyethyleneterephthalate, polyethylene, polypropylene, polyvinylchloride (PVC) andpolyvinylidene chloride (PVDC), but also of those of ethylene vinylacetate copolymer (EVA) with a preferably low portion of vinyl acetateof <10%. Films of very elastic hydrocarbon polymers such aspolyisobutylene, polyisoprene, or the block copolymers of styrene andisoprene or butadiene are also possible.

As backing layer, multilayered composite materials (laminates) with onlyone layer thereof consisting of the polymers mentioned, may also beused.

Finally, it is also possible to use the backing layer as a controlmembrane by adjusting a defined, low water vapour permeability. Thisenables a defined retardation of the retaining of moisture, and therebyof activation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1–13 depict various embodiments of the therapeutic systems of theinvention.

FIG. 14A depicts a dehydration profile of Na₂SiO₃.5H₂O.

FIG. 14B depicts a dehydration profile of Na₂Si₃O₇.xH₂O.

FIG. 14C depicts a dehydration profile of Na₃PO₄.12H₂O.

FIG. 15 depicts a permeation profile of therapeutic systems with andwithout an activator.

FIG. 16 depicts a permeation profile of various embodiments of thetherapeutic systems of the invention.

FIG. 17 depicts a permeation profile comparing the effects of hydratedand dried activator.

FIG. 18 depicts the stability of ropinirole without activator.

FIG. 19 depicts the stability of ropinirole with activator.

FIG. 20 depicts the effect of various concentrations of isopropylmyristate on a permeation profile of ropinirole.

Examples of layered structures will be described in the following withreference to the Figures.

If active substance (11) and activator (12) are introduced into onelayer, this layer (1), in a particularly preferred configuration,possesses pressure-sensitive adhesive properties at the same time, sothat no separate adhesive layer is necessary (system A, FIG. 1).

The system A then only consists of a detachable protective layer, apressure-sensitive adhesive layer containing active agent and activator,as well as a backing layer (2).

After application to the skin, dissolution of the activator occurs underabsorption of moisture; the activator up to that moment having beenpresent in a hydrated but undissolved state. The dissolved activatordiffuses to the active substance, which is present in salt form, andtransforms the same into the form of a free acid or free base. This freeform diffuses through the pressure-sensitive adhesive layer to the skinand there is taken up into the body.

As an alternative, it is also possible for the active substance salt tobe dissolved by the absorption of moisture and to diffuse to theactivator. There, it is converted into the free acid or base of theactive substance, which represents the form of the active substancewhich is better capable of penetrating the skin, and is subsequentlydelivered to the skin by diffusion.

System A may alternatively be equipped with a control layer (3) (systemB, FIG. 2).

The control layer either controls the absorption of moisture and therebythe activation itself, or alternatively the active substance release andthereby the release behaviour after activation. In the structureillustrated, the control layer simultaneously possessespressure-sensitive adhesive properties and serves to fix the system onthe skin.

Optionally, this control function can also be performed by a layerenveloping the active substance or the activator in dispersed state(systems C and D, FIGS. 3 and 4).

Should the active agent or the activator be incompatible with thepressure-sensitive adhesive layer, it is preferable to add a separatepressure-sensitive adhesive layer (5) on the side facing the skin(system E, FIG. 5). This addition of a pressure-sensitive adhesive layeris, by analogy, also applicable to systems A–D.

The additional pressure-sensitive adhesive layer does not need to beconfigured throughout the entire surface. The anchoring of the system onthe skin may also be effected by a pressure sensitive adhesive layer (6)projecting outwardly beyond the reservoir layer (system F, FIG. 6). Thisprocedure, too, is applicable to the systems A–D.

In order to obtain a certain activation or release behaviour, it may benecessary to incorporate the active agent and the activator in separatelayers of the TTS. In the preferred case, one of these two reservoirlayers, i.e. layer (7) containing the active substance or layer (8)containing the activator, is simultaneously the pressure-sensitiveadhesive layer which enables the system to be anchored on the skin.Either the active substance is present in a layer nearer to the skinthan that of the activator (system G, FIG. 7), or vice versa (system H,FIG. 8).

With structures of this kind, the activator is dissolved underabsorption of moisture, diffuses into the neighbouring layer to theactive substance, which is present in salt form, and liberates therefromthe base or acid. This free form then diffuses toward the skin and viathe skin enters the body. Alternatively, dissolution of the activesubstance may occur, said active substance diffusing into theneighbouring layer towards the activator and being converted by saidactivator into the free base or acid. To control the access of activesubstance to the activator, or the reversed process, it may be useful toprovide a control layer (3) which is arranged between the two reservoirlayers for active substance and activator (system I, FIG. 9). Theprinciple can, by analogy, also be applied to the system H.

The control layer may also be provided as the layer (3) nearest to theskin and, if it also has pressure-sensitive adhesive properties, serveto anchor the entire system on the skin (system J, FIG. 10).

Instead of introducing separate control layers, it is also possible toenclose the active substance or the activator in dispersed state with acontrol layer (4), by analogy to systems C and D (system K, FIG. 11).

Should neither the active substance nor the activator be compatible witha suitable pressure-sensitive adhesive, it may be required to introducea separate pressure-sensitive adhesive layer (5) (system L, FIG. 12).

This structure is by analogy, applicable to systems G–K.

Finally, it is also possible to provide, instead of a full-surfaceskin-facing pressure-sensitive adhesive layer, a pressure-sensitiveadhesive layer (6) which overlaps the reservoir layers only in themarginal areas, by analogy to system F (system M, FIG. 13). Thisapproach, too, is, by analogy, applicable to systems G–K.

Preferably, a TTS constructed according to the present invention has thestructure as described in the following: The overall constructionfollows FIG. 1. The active agent and the activating agent in theirrespective first chemical states are present as solids, dispersed sideby side in a single matrix layer. This matrix layer has at the same timepressure-sensitive adhesive properties and serves to fix the system onthe skin. The pressure-sensitive adhesive matrix is preferably based ona silicone rubber.

The active substance in its non-ionic form is a chemical base, and thisbasic form has little chemical stability. The activating agent in itsfirst state is a basic-reacting substance; it is preferably an alkalineearth metasilicate or alkaline earth trisilicate in a hydrated form.

The backing layer of the TTS consists of an almost watervapour-impermeable film, preferably of polyethylene terephthalate (PET),or of a laminate of 2 layers of which one is made of PET.

The primary packaging of the TTS possesses a barrier action to watervapour that is as high as possible in order to prevent prematureactivation during storage.

EXAMPLES

1. Activators

Of the basic activators described, the silicates and phosphates are, dueto their particular water-binding capacity, particularly suitable.

The dehydration behaviour of these substances was examined in threeexample substances by Difference Scanning Calorimetry (DSC). Thisthermal analysis provides information on the stages of dehydrationtaking place under energy absorption, and on the respective typicaltemperature.

Na₂SiO₃.5H₂O dehydrates substantially at 86.5° C. (FIG. 14 a). WithNa₂Si₃O₇.xH₂O this does not occur until 101.2° C. (FIG. 14 b).

In the case of Na₃PO₄.12H₂O there is observed a multiple-stagedehydration which takes place mainly at 93.6° C. and 117.6° C. (FIG. 14c).

2. Transdermal Therapeutic System (TTS)

All of the activating agents and therapeutic agents used in the examplesystems were milled in a blade disintegrator and passed through a sieveof a mesh width of 50 μm prior to use. This was necessary in order to beable to spread the preparations in thin layers and to achieve a uniformdistribution in the finished product.

2.1. Example TTS Comprising SDZ ENA713 as Active Agent

An example TTS was developed for delivery of the active substance SDZENA713 to the skin. SDZ ENA713 is a research substance of the firm ofNovartis for treatment of Alzheimer's disease.

The basic substance was utilized in form of the hydrogen tartrate salt.In a structure corresponding to system A, this active substance salt wasincorporated, along with the activator sodium metasilicate, into asilicone-based pressure-sensitive adhesive.

Composition of the pressure-sensitive adhesive layer (%−wt. of driedmatrix):

Formulation I II III ENA 713 Hydrogen Tartrate 10 10 10 Na₂SiO₃ —  3 —Na₂SiO₃.5H₂O — —  3 Bio-PSA Q7-4301 90 87 87

Bio-PSA Q7-4301 is a medicinal pressure-sensitive adhesive on the basisof polydimethyl siloxane (Dow Corning).

The active substance and, optionally, the activator were added to thesolution of the adhesive in benzine. By stirring, a homogenousdispersion was obtained. This dispersion was coated on a suitableflat-shaped carrier (in the example: ScotchPak 1022—a polyethyleneterephthalate film by the firm of 3M with a dehesive coating on basis offluorinated polymers).

Drying took place for 10 minutes at room temperature and for 10 minutesat 50° C., in an exhaust air drying cupboard. The weight per unit areaof the matrix was typically 60 g/m².

The exposed side of the dried matrix was laminated with a suitable film(in the example: Hostaphan RN 15—a polyethylene terephthalate film byHoechst).

Formulations I–III were used in in-vitro permeation tests on the modelof bovine udder skin (n=3). Static, two-chamber diffusion cells of themodified Franz cell type as generally known in the field of TTS researchand development were used.

The resultant permeation profiles are shown in FIG. 15. Whilst theactive substance salt without activator salt is released only in a verysmall amount, under the influence of the activators a controlledpermeation takes place. In the hydrated state (pentahydrate), theactivator here leads to a markedly earlier onset of the active substancerelease and to an overall active substance release higher than thatobtained by the water-free activator.

2.2 Example TTS Comprising Ropinirole as Active Substance

Ropinirole is a basic active agent by SmithKline Beecham for treatingParkinson's disease. In the form of its free base, ropinirole ischemically very unstable and is therefore hardly suitable for processingand storage in a TTS.

A moisture-activatable TTS was developed containing the hydrochlorideinstead of the free base. As activators, sodium trisilicate and variousbasic sodium phosphates were tested.

Composition of the pressure-sensitive adhesive layer (%−wt of the driedmatrix):

Formulation IV V VI VII VIII IX Ropinirole HCl 10.0 10.0 10.0 10.0 10.010.0 Na₂Si₃O₇ — — — — —  6.0 Na₂Si₃O₇.XH₂O*  6.0 — — — — — Na₂SiO₃.5H₂O—  5.2 — — — — Na₂HPO₄.2H₂O — —  6.0  3.0 — — Na₃PO₄.12H₂O — — —  6.4 6.4 — Isopropyl Myristate  1.0  1.0  1.0  1.0  1.0  1.0 Bio-PSA Q7-430183.0 83.3 83.0 79.6 82.6 83.0 *The bound water corresponds to 10%-wt. ofthe substance.

The active substance and possibly the activator were added to thesolution of the adhesive in benzine, into which the liquid isopropylmyristate had been added previously. A homogenous suspension wasobtained by stirring.

This suspension was coated on an appropriate flat carrier (in theexample: ScotchPak 1022).

Drying took place for 10 minutes at room temperature and for 10 minutesat 80° C., in an exhaust air drying cupboard. The weight per unit areaof the dried matrix was typically 60 g/m².

The exposed side of the dried matrix is laminated with a suitable film(in the example: Hostaphan RN15)

Formulations IV–VIII were used in in-vitro permeation tests on humanfull-thickness skin in modified Franz cells (n=3).

The resultant permeation profiles are shown in FIG. 16. As activators,the silicates used generally prove to be clearly superior to thephosphates.

Of the phosphate-containing formulations, the mixture of the two basicphosphates (VII) surprisingly yields the best results, although the puretriphosphate (VIII) should react more strongly basic under moistureabsorption and should thus cause a stronger activation of ropinirole.

The further examination showed that the hydrate water content in thesodium trisilicate has a clearly positive effect on the activatorfunction.

If this auxiliary agent is dehydrated for 2 hours at 130° C. prior toits use (formulation IX), the activation process is delayed.

This finding could be confirmed in vitro on human full-thickness skin of2 different individuals (n=3; FIG. 17). The hydrate water content alonecaused an increase in permeation after 24 hours by 33% and 37%,respectively, as compared to the water-free form of the activator.

Conventional and moisture-activatable TTSs with ropinirole as activesubstance were examined as to stability.

The following formulations were tested:

Formulation X XI XII XIII Ropinirole Base  8.0** — — — Ropinirole HCl — 6.3** 10.0 10.0  Na₂Si₃O₇.XH₂O* — 2.9  6.0 — Na₂HPO₄.2H₂O — — — 3.0Na₃PO₄.12H₂O — — — 6.4 Isopropyl Myristate 2.0 2.0  2.0 2.0 Bio-PSAQ7-4301 90.0  88.8  82.0 88.6  *The bound water corresponds to 10%-wt.of the substance. **The active substance content of the formulationscontaining dissolved free base is dependent on the maximum amount to beintroduced in the respective process. In the case ofcrystalline-suspended active substance salt, the content was arbitrarilychosen to be 10%.

Formulation X was prepared by emulsifying oily ropinirole base in thebenzine adhesive solution, and by coating and drying this solution.

Ropinirole base was initially isolated from the hydrochloride salt asfollows:

A solution of 10.0 g of ropinirole hydrochlorid in 100 ml of water wasadjusted to a pH of 10–11 by dripping in 5 N aqueous NaOH solution.

This solution was extracted twice in succession with 50 ml of diethylether at a time; the two ether phases were united.

The ethereal solution of ropinirole base was dried with water-freeNa₂SO₄, filtered off and subsequently narrowed down to dryness in anitrogen stream.

The oily residue was redried and finally left to crystallise in therefrigerator at 4° C. This yielded 8.94 g of ropinirole base or 99% ofthe theory. The melting point was determined at 73° C. (DSC), purity was98% (HPLC).

With formulation XI, ropinirole HCl and sodium trisilicate wereinitially mixed with a small amount of ethanol and left to react for 18hours at room temperature and under absence of light, while stirring.This pre-solution was then mixed in a corresponding amount with thebenzine solution of the adhesive, coated and dried.

The preparation of formulations XII and XIII is analogous to thepreparation of formulations IV to VIII.

Concerning the conditions of coating and drying as well as the filmmaterials used in formulations X to XIII, reference is likewise made toformulations IV to VIII.

Already after one month's storage, the following picture results (n=6):

The free base ropinirole proves to be too unstable for a marketableproduct (formulation X, FIG. 18), even if a pure silicone adhesivewithout further additives is used.

This also applies if ropinirole is utilised in the salt form of thehydrochloride but the base is released therefrom by the activatoralready during the manufacture of the TTS (formulation XI, FIG. 19).

If aqueous sodium trisilicate is used, the presence of ethanol (which inusual quality always contains small amounts of water) already sufficesto trigger the conversion of ropinirole hydrochloride into the base.This reaction, which takes place readily, leads to the realization thatfor preparing the TTS according to the invention, there should beutilised aprotic solvents which are as nonpolar as possible. In thismanner it is possible to prevent an unwanted premature onset of thetransformation of the active substance salt into the base. Such solventsare preferably ethyl acetate, pentane, hexane, cyclohexane, heptane,octane, toluol and xylol, dichloromethane and chloroform as well asbenzine of various boiling ranges.

The moisture-activatable formulations XII and XIII, prepared in benzinesolution, according to the data show a considerably improved stabilitywhich is sufficient for a marketable product (n=6, FIG. 19) after 2 and4 months of storage. Obviously, the release of the base only takes placeto a negligible extent, if at all, during the manufacture of the TTS.

With formulations comprising ropinirole as active substance it wasfurther found that the course of moisture activation can obviously bemodified by small amounts of certain additives. Thus, addition of verysmall amounts of isopropyl myristate already causes acceleratedactivation and correspondingly increased overall permeation in vitro.The following formulations were tested on bovine udder skin in vitro(n=3):

Formulation XIV XV XVI XVII XVIII Ropinirole HCl 10.0 10.0 10.0 10.010.0 Na₂Si₃O₇.XH₂O*  6.0  6.0  6.0  6.0  6.0 Isopropyl Myristate —  0.5 1.0  2.0  4.0 Bio-PSA Q7-4301 84.0 83.5 83.0 82.0 80.0 *The bound watercorresponds to 10%-wt. of the substance.

The manufacture was performed according to the indications made withrespect to formulations IV to VIII.

The result shows that surprisingly small additions of isopropylmyristate already lead to accelerated activation. The effect is clearlycorrelated with the quantity of isopropyl myristate (FIG. 20).

Although in the past, isopropyl myristate as permeation enhancer hasbeen observed and described in many cases, such an effect influencingthe condition of the skin has hitherto never been found forconcentrations of only 0.5%. What is more likely is an effect modulatingthe acid-base reaction which takes place under access of moisture, whicheffect can be utilised here. As a consequence, there is the possibilityof modulating the moisture-activatable systems according to theinvention by using appropriate additives in the course of activation.

1. A therapeutic system for timed and controlled release of at least onetherapeutic active agent to a human or animal organism by means ofdiffusion through the skin or mucous membrane, said active agentinitially being present, for the purpose of manufacture and storage, ina first state in which it is chemically stable and insufficientlypermeable for the skin or mucous membrane, whereas it is converted atthe application site into a second state by access of moisture, in whichstate it is suitable for diffusion through the skin or mucous membraneand in which it is taken up by the organism, wherein said active agentin said first state is contained in the system as a pharmaceuticallyacceptable acid salt which is present dispersed as an undissolved solidand which upon access of emerging skin or mucous moisture and by a basicactivating agent, which is likewise contained in the system, ischemically converted into the said second state of a base which is takenup through the skin or mucous membrane into the organism in anaccelerated manner and in greater quantities compared to the acid saltform, said basic activating agent is selected from a hydrated butundissolved form of a base consisting of sodium trisilicate, sodiummetasilicate, disodium phosphate (secondary sodium phosphate), trisodiumphosphate (tertiary sodium phosphate), tripotassium phosphate, magnesiumcarbonate hydroxide, aluminium magnesium hydroxide sulfate, trisodiumcitrate dehydrate, magnesium citrate tetradecahydrate, tetrasodiumedentate dehydrate, potassium sodium tartrate tetrahydrate and disodiumsuccinate hexahydrate, wherein said basic activating agent has eitherintercalated or bound water of at least 5% to about 60% in its solidbody structure.
 2. The therapeutic system according to claim 1,characterized in that the moisture present at the application site is aliquid which is actively released by the skin via the sweat glands, orwater vapor which is passively released in the form of a gas via theskin surface, and that in the case of mucous membranes, said moistureare body liquids secreted by glands.
 3. The therapeutic system accordingto claim 1, characterized in that the therapeutic active agent ispresent in an amount of 0.5 to 50%, of the overall weight.
 4. Thetherapeutic according to claim 1, characterized in that the ratio ofactivating agent to the therapeutic agent is 0.1 to 10, relative to thestoichiometry of the chemical reaction.
 5. The therapeutic systemaccording to claim 1, characterized in that both the therapeuticallyactive agent and the activating agent are contained in substantiallyundissolved form.
 6. The therapeutic system according to claim 5,characterized in that agents present in undissolved form have a particlesize of between 1 and 200 μm.
 7. The therapeutic system according toclaim 6, characterized in that the therapeutic agent and the activatingagent are uniformly dispersed in a matrix, wherein the matrix is a layerof the transdermal therapeutic system.
 8. The therapeutic systemaccording to claim 7, characterized in that a matrix layer or a controllayer possesses pressure-sensitive adhesive or mucoadhesive properties.9. The therapeutic system according to claim 6, characterized in thatthe therapeutic active agent and the activating agent are present inseparate matrix layers.
 10. The therapeutic system according to claim 9,characterized in that one of the two matrices is in direct contact withthe skin or mucous membrane.
 11. The therapeutic system according toclaim 10, characterized in that the matrix layer intended for contactwith the skin possesses pressure-sensitive adhesive or mucoadhesiveproperties.
 12. The therapeutic system according to claim 1,characterized in that it further comprises a control layer which is freeof the therapeutically active agent and the activating agent.
 13. Thetherapeutic system according to claim 12, characterized in that thecontrol layer is arranged such that it is in direct contact with theskin or mucous membrane when the system is applied.
 14. The therapeuticsystem according to claim 12, characterized in that the control layer isconfigured and arranged such that it controls the extent and speed ofthe absorption of moisture from the site of application into the system.15. The therapeutic system according to claim 12, characterized in thatthe control layer is configured and arranged such that it controls theextent and speed of the diffusion of the therapeutically active agent inits activated form out of the system to the application site.
 16. Thetherapeutic system according to claim 12, characterized in that thecontrol layer is inserted between the therapeutically active agent andthe activating agent.
 17. The therapeutic system according to claim 12,characterized in that the control layer constitutes a plurality ofspherical single layers of identical composition which envelope theundissolved, dispersed therapeutically active agent or the undissolved,dispersed activating agent.
 18. The therapeutic system according toclaim 12, characterized in that the control layer is configured andarranged such that it controls the extent and speed of the diffusion ofthe activating agent in its dissolved form towards the therapeuticallyactive agent.
 19. The therapeutic system according to claim 12,characterized in that the control layer is configured and arranged suchthat it controls the extent and speed of the diffusion of thetherapeutically active agent in its dissolved form towards theactivating agent.
 20. The therapeutic system according to claim 1,characterized in that the therapeutically active agent is ropinirolehydrochloride or another pharmaceutically acceptable salt of ropinirole.21. The therapeutic system according to claim 6, characterized in thatthe matrix layer consists of a formulation based on silicone rubber,polyisobutylene, polyisoprene, or a block copolymer of styrene withisoprene or butadiene.
 22. The therapeutic system according to claim 3,wherein the amount of therapeutic agent is 1.0 to 20% of the overallweight.
 23. The therapeutic system according to claim 4, wherein theratio is 0.2 to 2.0.
 24. The therapeutic system according to claim 6,wherein the particle size is between 2 and 50 μm.
 25. The therapeuticsystem according to claim 6, characterized in that the therapeutic agentis substantially dissolved upon access of moisture and then diffuses tothe activating agent within the therapeutic system where saidtherapeutic agent is converted into the form of the acid or base, whichchemically corresponds to the pharmaceutically acceptable salt of thetherapeutic agent, by the activating agent.
 26. The therapeutic systemaccording to claim 6, characterized in that the activating agent, whichis present as a pharmaceutically acceptable salt, is substantiallydissolved and then diffuses to the therapeutic agent within thetherapeutic system, where said activating agent converts saidtherapeutic agent into the form of the acid or base, which chemicallycorresponds to the pharmaceutically acceptable salt of said therapeuticagent.
 27. The therapeutic system according to claim 1, wherein saidtherapeutic system further comprises a fatty acid ester of a short-chainalcohol in an amount between 0.5 and 5.0% by weight.
 28. The therapeuticsystem according to claim 27, characterized in that the esters areformed from a saturated or mono-unsaturated carboxylic acid with 6 to 18carbon atoms and an alcohol with 1 to 3 carbon atoms having maximallyone hydroxyl group per carbon atom.
 29. The therapeutic systemsaccording to claim 28, wherein the alcohol molecule is furtheresterified and the ester is isopropyl myristate, isopropyl palmitate, asaturated triglyceride, glycerin monolaurate or glycerin monoleate.